Numerical simulation of the cavopulmonary connection flow with conduit stenoses of varying configurations.

The circulation in the total cavopulmonary connection (TCPC) is a low-energy system which operation and efficiency are subjected to multiple factors. Some retrospective studies report that the abnormal narrowing of vessels in the system, i.e. stenosis, is one of the most dangerous geometric factors which can result in heart failure. In the present study, the effect of varying extracardiac conduit (ECC) stenosis on the hemodynamics in a surrogate TCPC model is investigated using high-fidelity numerical simulations. The efficiency of the surrogate TCPC model was quantified according to the power loss, relative perfusion in lungs and the percentage of conduit surface area with abnormally low and high wall shear stress for venous flow. Additionally, the impact of respiration and asymmetry in the stenosis geometry to the system was examined. The results show that the flow in the TCPC model exhibits pronounced unsteadiness even under the steady initial boundary conditions, while the uneven pulmonary flow distribution and the presence of the ECC stenosis amplify the chaotic nature of the flow. Energy efficiency of the system is shown to strongly correlate with amount of vortical structures in the model and their range of scales. Finally, the study demonstrates that the presence of respiration in the model adds to perturbations in the flow which causes increase in the power loss. Results obtained in the study provide valuable insights on how the ECC stenosis effect the flow in the surrogate TCPC model under different flow conditions.

A microfluidic method to investigate platelet mechanotransduction under extensional strain.

Background: Blood platelets have evolved a complex mechanotransduction machinery to rapidly respond to hemodynamic conditions. A variety of microfluidic flow-based approaches have been developed to explore platelet mechanotransduction; however, these experimental models primarily focus on the effects of increased wall shear stress on platelet adhesion events and do not consider the critical effects of extensional strain on platelet activation in free flow. Objectives: We report the development and application of a hyperbolic microfluidic assay that allows for investigation of platelet mechanotransduction under quasi-homogenous extensional strain rates in the absence of surface adhesions. Methods: Using a combined computational fluid dynamic and experimental microfluidic approach, we explore 5 extensional strain regimes (geometries) and their effect on platelet calcium signal transduction. Results: We demonstrate that in the absence of canonical adhesion, receptor engagement platelets are highly sensitive to both initial increase and subsequent decrease in extensional strain rates within the range of 747 to 3319/s. Furthermore, we demonstrate that platelets rapidly respond to the rate of change in extensional strain and define a threshold of ≥7.33 × 106/s/m, with an optimal range of 9.21 × 107 to 1.32 × 108/s/m. In addition, we demonstrate a key role of both the actin-based cytoskeleton and annular microtubules in the modulation of extensional strain-mediated platelet mechanotransduction. Conclusion: This method opens a window onto a novel platelet signal transduction mechanism and may have potential diagnostic utility in the identification of patients who are prone to thromboembolic complications associated with high-grade arterial stenosis or are on mechanical circulatory support systems, for which the extensional strain rate is a predominant hemodynamic driver.

An extensional strain sensing mechanosome drives adhesion-independent platelet activation at supraphysiological hemodynamic gradients.

BACKGROUND: Supraphysiological hemodynamics are a recognized driver of platelet activation and thrombosis at high-grade stenosis and in blood contacting circulatory support devices. However, whether platelets mechano-sense hemodynamic parameters directly in free flow (in the absence of adhesion receptor engagement), the specific hemodynamic parameters at play, the precise timing of activation, and the signaling mechanism(s) involved remain poorly elucidated. RESULTS: Using a generalized Newtonian computational model in combination with microfluidic models of flow acceleration and quasi-homogenous extensional strain, we demonstrate that platelets directly mechano-sense acute changes in free-flow extensional strain independent of shear strain, platelet amplification loops, von Willebrand factor, and canonical adhesion receptor engagement. We define an extensional strain sensing "mechanosome" in platelets involving cooperative Ca2+ signaling driven by the mechanosensitive channel Piezo1 (as the primary strain sensor) and the fast ATP gated channel P2X1 (as the secondary signal amplifier). We demonstrate that type II PI3 kinase C2α activity (acting as a "clutch") couples extensional strain to the mechanosome. CONCLUSIONS: Our findings suggest that platelets are adapted to rapidly respond to supraphysiological extensional strain dynamics, rather than the peak magnitude of imposed wall shear stress. In the context of overall platelet activation and thrombosis, we posit that "extensional strain sensing" acts as a priming mechanism in response to threshold levels of extensional strain allowing platelets to form downstream adhesive interactions more rapidly under the limiting effects of supraphysiological hemodynamics.